Abstract The current epidemic of opioid-related deaths ravaging the nation demands innovative new approaches to treat opioid use disorders and prevent deaths resulting from accidental overdose. Patients with a history of opioid use followed by a period of sobriety are at particularly high risk for overdose. This increased risk stems from the development of tolerance during prolonged periods of use. Tolerance can quickly fade during a period of abstinence, so if a patient relapses and takes the same dose used prior to the period of abstinence, the dose will be high enough to precipitate an acute respiratory crisis, leading to injury or death. Current treatment requires administration of naloxone by first responders. This treatment requires timely identification of the overdose and need for a rescue injection, as well as the immediate availability of the medication. The development of a fail- safe treatment that would provide a life-saving dose of naloxone without the need for intervention by another party could significantly reduce mortality. In the present application, we propose the development of a new medical device comprising an implantable, closed-loop system that senses the presence of an opioid overdose, and automatically administers a life-saving bolus injection of naloxone, and simultaneously alerts first responders. This proposal builds on technologies that the investigative team has developed over the past several years.